Acutely ill individuals experience cognitive deficits, malaise, and lethargy. Sick individuals also exhibit profound changes in sleep with reduced motor activity, they become anorexic, and they lose interest in social contact and other usual daily activities. Collectively, this constellation of symptoms is referred to as sickness behavior. Cytokines such as interleukin (IL)-I, IL-6, and tumor necrosis factor (TNF), act in brain to induce many of the sequelae of sickness behavior. Although phylogenetic data and conventional wisdom suggest that sickness behavior during acute infection promotes survival, few studies have tested this hypothesis. The fundamental goal of this project is to determine how immune responses to acute infection impact central nervous system (CNS) function. Many of the behavioral responses to immune challenge described above are manifest during the development of sepsis. Previous work, and studies proposed in other projects of this PPG application, focused on inflammatory mediators in the peritoneum. The central hypothesis to be tested by experiments in this project is that brain responses to sepsis are a critical determinant of clinical outcome. We will use a dual approach to test this central hypothesis: 1) pre-clinical experiments will be conducted in mice using the well-defined model of sepsis induced by cecal ligation and puncture (CLP); 2) patients presenting to the Trauma and Burn ICU will be recruited for continuous EEG recordings. Using this parallel approach, we will: quantify in mice the extent to which behavior is altered by the infectious process (Specific Aim 1), determine how selected cytokines and their regulatory mechanisms in brain promote or inhibit specific aspects of sickness behavior of mice, and how interfering with their actions impacts survival (Specific Aim 2), and determine in both mice and ICU patients the degree to which sleep disruption and sedation alter immune responses, sickness behavior and survival (Specific Aim 3). We have demonstrated our ability to obtain similar and overlapping measures from mice and from acutely ill patients. This capability represents a powerful tool for translational studies of the role of the CNS in responses to sepsis. Given that the brain and the peripheral immune system engage in bi-directional communication, determination of how brain status influences systemic immune responses to sepsis may provide insight into new therapeutic interventions so that sepsis may be more frequently followed by recovery.